Hepatitis B vaccine efficacy in children exposed to anti-TNF in utero

Biological agents like anti-TNF have revolutionized the treatment of
Inflammatory Bowel Disease (IBD) by successfully achieving and maintaining
remission (1). IBD typically affects people at a young childbearing age (2),
therefore some IBD women will require biological therapy during pregnancy.
Anti-TNF agents have been accepted as generally safe during pregnancy as they
do not give rise to an increased risk of congenital abnormalities, preterm
birth, low birth weight or miscarriages (3, 4), however there are several long
term effects left unexplored.
Several studies have demonstrated anti-TNF to actively cross the placenta in
the second and especially the third trimester of pregnancy (5-7). Consequently,
children from anti-TNF treated mothers are born with clinically significant
serum levels of anti-TNF.
A shocking case-report in 2010 (8) describing a fatal case of disseminated BCG
disease in a child born to a mother deliberately treated with anti-TNF during
pregnancy, has led to the avoidance or delay of administering live attenuated
vaccines in these children. However, the efficacy of other passive vaccines,
like the hepatitis B (HBV) vaccine, is unknown in children of this specific
group of patients.
There is evidence that the HBV vaccine in adult and paediatric IBD patients
treated with anti-TNF fails to yield adequate immunologic response after
primary vaccination (9-12). Adequate anti-Hbs levels are not present in
approximately half of these patients, and in the pediatric IBD patients on
anti-TNF 14% did also not respond to a booster vaccine(9). Response to the
hepatitis B vaccine has not yet been investigated in neonates born to mothers
treated with anti-TNF during pregnancy. The aim of this study is therefore to
assess response to the HBV vaccine in children born to IBD mothers treated with
anti-TNF during pregnancy in terms of anti-Hbs levels after the final dose of
the hepatitis B vaccine. These outcome measures will be compared to a control
group of IBD mothers treated with other medication than anti-TNF and their
children.

Primary Objective:
- Antibodies to the hepatitis B surface antigen (anti-HBs) levels 30 days after
the last hepatitis B vaccine dose (11 months) in children from IBD mothers
treated with anti-TNF compared to children from IBD mothers not treated with
anti-TNF.

Secondary Objective:
- (if required) anti-HBs levels after HBV booster vaccine in case of primary
non-immunity
- Anti-TNF levels from the cord blood, and if required when the child is 3
months old, 6 months old and 12 months old.
- Maternal anti-TNF levels at delivery

We propose a single center, cross sectional study. Pregnant women with IBD
treated with anti-TNF during pregnancy who visit the preconception outpatient
clinic (POC) will be informed about this study and asked to participate. These
women will be asked if they intend to vaccinate their child according to the
national vaccination programme (Rijksvaccinatie programma). We will obtain
informed consent and make arrangements for obtaining cord blood and maternal
peripheral blood at delivery. An appointment will be made at the Sophia*s
Children Hospital when the child is 3 months old, 6 months old and 1 year old.
At month 3 and 6, anti-TNF serum levels will be determined if the cord blood
anti-TNF level exceeds 3 µg/mL and at 12 months anti-Hbs levels will be
assessed. The anti-TNF level assessment is part of standard medical care.

Study subjects (mother and child) will not have direct benefits from
participating in this study. The burden associated with this study entails a
visit at the Sophia Children*s Hospital when the child is 12 months old. At
this visit, a blood sample will be obtained for assessment of anti-HBs levels.
If the child proves to be non-immune for HBV, 4 weeks after a HBV booster
vaccination another appointment at the Sophia*s Children Hospital will be made
to obtain another blood sample. The cord blood and possible follow up visits to
obtain blood to assess the anti-TNF levels are part of standard medical care
and thusly do not count as burden for this study.
This study is exclusively bound to this specific population of pregnant IBD
patients and their children. Data from other studies with a similar research
question in adults and older children cannot be extrapolated to this
population, because of their age and underlying disease. The aimed study
population in this study are healthy neonates, born with clinically significant
immunosuppressive medication.